Role of the GSK3-NRF2 axis in beta cell decline in type 2 diabetes

Type 2 diabetes occurs when insulin production from pancreatic beta cells is insufficient to prevent the hyperglycemia that defines diabetes.

Insulin production declines during progression of the disease, resulting in worsening glucose control and poorer responses to available therapeutic strategies.

Recent work in models of type 2 diabetes has implicated the protein kinase GSK3 and the cytoprotective transcription factor Nrf2, in the development of beta cell defects and type 2 diabetes. Our group has discovered that GSK3 modifies Nrf2, promoting its degradation.

We propose that this ‘GSK3-Nrf2 interaction’ is a key regulator of beta cell biology, and its disruption contributes to development of diabetes.

The proposed project will generate mechanistic supporting evidence for this hypothesis, with the aim to identify novel opportunities to prevent beta cell damage in type 2 diabetes.

Specifically, we will establish whether the GSK3 regulation of Nrf2 in vitroinfluences beta cell function, growth and survival.

Moreover, we will assess beta cell function, growth and survival, and progression toward type 2 diabetes, following beta cell-specific genetic manipulation of Nrf2 in vivo. These data will clarify the therapeutic potential for modification of this pathway in the treatment of diabetes.